1. Field of the Invention
This invention relates to pharmaceutical compositions for transdermal and transmucosal administration of prostaglandins to a patient, as well as the use of such compositions for the amelioration of human female sexual dysfunction.
2. Background of the Invention
Sexual dysfunction has been a persistent problem, more frequent in an aging population, that has only recently been addressed with frank evaluation, scientific investigation and effective treatment. Male impotence, especially male erectile dysfunction, has received the most attention. Female sexual dysfunction has been considered in the context of male erectile dysfunction, in part because of the anatomical and physiological parallels between the male and female genitalia, and in part, with the hope that effective treatments for male erectile dysfunction could provide some relief for female sexual dysfunction.
Both male and female sexual behavior is viewed from the standpoint of a four-phase sexual response cycle consisting of the stages of desire, excitement, orgasm and resolution. Studies have shown that while there are many similarities between male and female sexual response, significant differences exist. Specific dysfunctions have been correlated with the phases of the model. The female sexual response and its dysfunctions remain poorly understood.
Female sexual arousal disorder (FSAD) is the persistent or recurrent inability to attain, or to maintain, sufficient sexual excitement, which causes personal distress. It may be expressed as lack of subjective excitement, lack of genital response, such as lubrication and swelling, or lack of other somatic responses. Female sexual arousal disorder is one form of female sexual dysfunction, and is associated with the excitement phase.
While increased understanding of the pathophysiology of male erectile dysfunction has progressed rapidly in the past decade and led to new therapeutic modalities, little has been done to address similar issues in women. Cardiovascular risk factors have been shown to correlate with complaints of vaginal and clitoral dysfunction. Goldstein, M. K., et al.,: Gynecological factors in sexual dysfunction of the older woman. Clin Geriatr Med 7: 41-61, (1991); Sadeghi-Nejad, H., et al.: Impotence is a couple""s disease: studies in female sexual dysfunction. J Urol 155: 677A, (1996); Slob, A. K., et al.: Sexuality and psychophysiological functioning in women with diabetes mellitus. J Sex Marital Ther: 59-69, (1990).
The correlation of cardiovascular risk factors and complaints of vaginal and clitoral dysfunction have led to suggestions that a significant degree of female sexual dysfunction is due to vascular insufficiency and therefore amenable to treatment with vasoactive agents. The underlying foundations of the normal and dysfunctional female sexual response must be considered in the context of the anatomy and physiology, summarized below. See, generally, Goldstein, I., and Berman, J. R., Vasculogenic female sexual dysfunction: vaginal engorgement and clitoral erectile insufficiency syndromes, Int. J. Impotence Research 10: Suppl. 2, S84-S90 (1998).
Anatomy of the Vagina
The vagina is the canal that connects the uterus with the external genital organs. Its design easily accommodates penetration of a rigid penile erection. At the posterior end the rounded neck of the uterus, the cervix, projects into the space known as the formix or vaginal vault. Anteriorly, two pleats of sensitive tissue, the labia minora, surround the opening of the vagina and are further protected by larger folds known as the labia majora.
The walls of the vagina consist of three layersxe2x80x94an inner mucosa an aglandular mucous membrane epithelium, an intermediate, highly vascularized muscularis layer, and an outer supportive fibrous mesh. The vaginal mucosa is a mucous type stratified squamous cell epithelium that undergoes hormone-related cyclical changes, such as a slight keratinization of the superficial cells during the menstrual cycle. The muscularis portion comprises smooth muscle and an extensive arborization of blood vessels that may swell during intercourse. The surrounding fibrous layer provides structural support to the vagina; this layer consists of elastin and collagen fibers which allow for expansion of the vaginal vault during sexual arousal or childbirth. Large blood vessels run within the mucosa, and nerve plexuses are present within muscular and adventitial layers. The vagina has many rugae or folds that are necessary for the distensibility of the organ during intercourse and childbirth. Smaller ridges lend to the frictional tension which exists during intercourse.
The arterial supply to the vagina is derived from an extensive network of branching vessels surrounding it from all sides. The anterior branch of the internal iliac artery continually bifurcates as it descends through the pelvis with a series of the newly generated vessels, each supplying the vagina to some degree. After giving off an obturator artery branch, the umbilical, and the middle rectal arteries diverge off to supply a superior and inferior vesical artery, respectively. Between the umbilical and the mid-rectal branches there is a generation of a uterine artery, which further bifurcates to give the vaginal artery. The internal pudendal and accessory pudendal artery also send a branch to the vaginal artery. Finally, the common clitoral artery sends a branch to the vaginal muscularis.
The neurologic innervation of the vagina originates from two separate plexuses, the superior hypogastric plexus and the sacral plexus, The hypogastric nerve plexus descends on the great vessels spreading into an inferior hypogastric plexus, which systematically branches further into a uterovaginal nerve. The somatic pudendal nerve originates off the pelvic splanchnic branches from the secret plexus. Pudendal branching innervates the vagina towards the opening of the introitus as the perineal and posterior labial nerves.
Immunohistochemistry studies have been utilized to better understand the innervation of the human vaginal mucosa. In a study by Hilliges et al. using protein gene product 9.5, more distal areas of the vagina had significantly more nerve fibers compared to the more proximal parts, and the anterior wall showed a denser innervation than the posterior wall (Hilliges, M. et al., Innervation of the human vaginal mucosa as revealed by PGP 9.5 immunohistochemistry, Acta Anatomica 153: 119 (1995)). Graf et al studied the distribution patterns and the occurrence of helospectin and pituitary adenylate cyclase activating polypeptide (PACAP) immunoreactivity (Graf, A. H., et al. Helospectin and pituitary adenylate cyclase activating polypeptide in the human vagina, Regul. Pept. 55: 277 (1995)). They confirmed a dense network of vasoactive intestinal peptide (VIP) immunoreactive nerve fibers showing sub-populations of helospectin and LI-type PACAP. Nerve fibers of the vagina had previously been shown to be active in association with specific peptides which include VIP, peptide histidine methionine (PHM), calcitonin gene related peptide (CGPP), and galanin. Genital vasodilation and subsequent increase in vaginal blood flow and lubrication have been observed upon exposure of vessels to VIP. VIP has been implicated as the neurotransmitter for mediating vaginal vasodilation and the formation of lubricating fluid during sexual arousal. Helospectin and PACAP, a potent vasodilator, belong to the same peptide family as VIP and PHM, and recent observations have been made to the effect that distributions and co-localizations of helospectin and VEP as well as PACAP and VIP have been reported in the mammalian gastrointestinal tract.
The vaginal canal is lubricated primarily from a transudate originating from the subepithelial vascular bed passively transported through the interepithelial spaces, sometimes referred to as intercellular channels. Additional moistening during intercourse comes from secretion of the paired greater vestibular or Bartholin""s glands.
Estrogen effects on the maintenance and function of female genitalia have been well documented in studies. Estrogen receptors have been shown to exist throughout the vaginal epithelium, in stromal cells, and in the smooth muscle fibers in the muscularis. Weaker conformations of estrogen such as estriol appear more effective in stimulating the vagina as opposed to the uterus. Thickness and rugae of the vaginal wall, as well as vaginal lubrication, have been shown to be estrogen dependent. Although this fluid production has been shown to be hormone-dependent both in the resting state and during sexual excitement, quantitative changes apparently do not occur during the menstrual cycle. An insufficient amount of estrogen will result in thin vaginal walls more easily susceptible to trauma with a decreased ability to heal, as well as a drier and less acidic vaginal environment more vulnerable to infection. Vaginal dryness is associated with ovarian failure and is effectively controlled by estrogen replacement therapy. Some women who are not sexually active may not notice the extent of vaginal atrophy but when coitus does resume, pain and discomfort from intercourse can be considerable.
Anatomy of the Clitoris
The clitoris is the homologue of the penis arising from the embryological genital tubercle. The clitoris consists of a cylindrical, erectile organ composed of three parts: the outermost glans or head, the middle corpus or body, and the innermost crura. The glans of the clitoris is visualized as it emerges from the labia minora, which bifurcate to form the upper prepuce anteriorly and the lower fronulum posteriorly. The body of the clitoris consists of two paired corpora cavernosa of about 2.5 cm in length and lacks a corpus spongiosum. The body extends under the skin at the corona to the crura. The two crura of the clitoris, formed from the separation of the most proximal portions of the corpora in the perineum, attach bilaterally to the undersurface of the symphysis pubis at the ischiopubic rami.
A fibrous tunica albuginea ensheathes each corporal body made up of lacunar space sinusoids surrounded by trabecula of vascular smooth muscle and collagen connective tissue. No retractor clitoridis muscle exists in humans as it does in other animals such as cattle and sheep, however a supporting suspensory ligament does hold the clitoris in the introital region.
The main arterial supply to the clitoris is from the illo-hypogastric-pudendal arterial bed. The internal pudendal artery is the last anterior branch off the internal iliac artery. Distally, the internal pudendal artery traverses Alcock""s canal, a position of the obturator fascia and lies on the inner side in apposition to the ischio-pubic ramus. In this latter location, the artery is susceptible to blunt perineal trauma. The internal pudendal artery terminates as it supplies the inferior rectal and perineal artery, which supplies the labia. The common clitoral artery continues to the clitoris. This artery bifurcates into a dorsal clitoral artery and a cavernosal clitoral artery.
Autonomic efferent innervation of the clitoris passes from the pelvic and hypogastric nerves to the clitoris through the urogenital diaphragm. Pelvic nerve stimulation results in clitoral smooth muscle relaxation and arterial smooth muscle dilation. There is a rise in clitoral cavernosal artery inflow, an increase in clitoral intracavemous pressure which lead to tumescence and extrusion of the glans clitoris.
Anatomical studies using female rats have indicated that the major neuronal input to the clitoris was seen in spinal segments from L5-S1, and to a lesser extent in T12-L4 as well as S2-S4. When a label that is taken up by nerve terminals and transported retrogradely to the nerve cell bodies (pseudorabies virus) was injected into the clitoris, labeled nerve cell bodies were found in the brain in multiple locations, including the nucleus paragigantocellularis, raphe pallidus, raphe magnus, Barrington""s nucleus, ventrolateral central gray, hypothalamus, and the medial pre-optic region. This implies a multisynaptic circuit of neurons may be involved in clitoral neurological control rather than just a simple somatic reflex connection.
Morphological studies have been performed using wheat germ agglutinin conjugated with horseradish peroxidase (WGA/HRP) injected into the clitoris of the female cat to compare afferent pathways to the entire population of pudendal nerve afferents. Central projections of the clitoral afferents were identified in the L7-S3 segments with the most prominent labeling in S 1-S2. In the same study, electrophysiological analysis of the clitoris performed under constant mechanical pressure stimulation indicated both phasic and tonic discharges in L7-S2, but most prominently in S1. In contrast electrical stimulation of the clitoris evoked discharges at S1 only. The neurotransmitters mediating clitoral and arterial smooth muscle dilation remain undetermined, however preliminary studies suggest that nitric oxide is involved. Histochemical studies have revealed VIP and neuropeptide Y (NPY) immunoreactive nerves in the clitoral erectile tissues. Somatic sensory pathways originate from the clitoral skin. There exists a dense collection of Pacinian corpuscles innervated by rapidly adapting myelinated afferents, as well as Meissner""s corpuscles, Merckel tactile disks, and free nerve endings. These sensory afferents pass from the dorsal clitoral nerve to the pudendal nerve.
Physiology of Female Sexual Arousal
The female sexual response phase of arousal is not easily distinguished from the phase of desire until physiological changes begin to take place in the vagina and clitoris as well as other sexual organs. Sexual excitement and pleasure are accompanied by pelvic vasocongestion and swelling of the external genitalia including vaginal engorgement and clitoral erection.
Vaginal engorgement enables a process of plasma transudation to occur, allowing a flow through the epithelium and onto the vaginal surface. Plasma transudation results from the rising pressure in the vaginal capillary bed during the arousal state. In addition there is an increase in vaginal length and luminal diameter, especially in the distal ⅔ of the vaginal canal.
Dissociation of Genital Reflexes from Subjective Arousal
Central nervous system areas primarily implicated in sexual arousal, based on animal research, include the medial preoptic, anterior hypothalamic region and related limbic-hippocampal structures. Cognitive effects have been investigated, and in one study the results suggest that the greatest contribution to sexual arousal in the female results from cognitive processing of stimulus content and meaning, and not from peripheral vasocongestive feedback (Laan, E., et al., Determinants of subjective experience of sexual arousal in women. Feedback from genital arousal and erotic stimulus content, Psychophysiol. 32: 44-(1995)).
The distinction between local physiological aspects of sexual response, such as genital vasocongestion measured by vaginal photoplesmography, and subjective sexual arousal, measured by self-reporting rating scales and inventories has been clearly demonstrated in both normal and sexually dysfunctional women (Palace, E. M. and Goralka, B. B., Differential patterns of arousal in sexually functional and dysfunctional women: Physiological and subjective components of sexual response, Arch. Sexual Behav. 21: 135-159 (1992)). Several reliable and validated self-report inventories are recognized for measurement of female sexual function (Derogatis, L. R. and Conklin-Powers, B., Psychological assessment measures of female sexual functioning in clinical trials, Int. J. Impot. Res. 10 Suppl. 2: S 11-S116 (1998)).
There does not appear to be a relation between menstrual phases and physiologic arousability. Meuwissen and Over (Habituation and Dishabituation of Female Sexual Arousal, Behav. Res. Ther. 28: 217-(1990)) have found that neither film-induced nor fantasy-induced levels of sexual arousal varied significantly throughout the menstrual cycle. There are conflicting reports as well as to the habituation of the female sexual response. Some claim that levels of subjective and physiologic sexual arousal decrease over repeated exposure to sexual stimuli. Others could not elucidate similar results even after 21 trials, yet both concur that the subsequent presentation of a novel stimulus will increase the female sexual response. The desire for increased sexual performance on sexual arousal in functional women have been found to facilitate genital responses, most prominently with the stimulus of erotic fantasy as opposed to erotic film. Interestingly, masturbation frequency had no affect on genital responses despite its significance on subjective reports of arousal. (Laan et al, 1995; Meuwissen and Over, 1990).
Clinicians and researchers have assumed that sexual arousal, is inhibited by the sympathetic nervous system, while facilitation and maintenance are through the parasympathetic nervous system. However, studies have challenged these notions in the woman. Intense exercise, consisting of twenty-minute bike riding sessions, increased physiological sexual arousal measured by vaginal photoplethysmography. This challenged the notion that sympathetic nervous system stimulation inhibited sexual arousal in women and further provided evidence that sexual arousal was actually facilitated by the sympathetic nervous system. Another study examined the temporal effect of sympathetic activation through acute exercise on immediate delayed, and residual sexual arousal. Sexual arousal was objectively assessed by vaginal plethysmography. A relationship between sympathetic nervous system activation and sexual arousal was found, such that sexual arousability was inhibited five minutes post-exercise and was facilitated fifteen minutes post-exercise and only marginally increased thirty minutes post-exercise. The two studies suggest that sympathetic nerve stimulation activation plays an important facilitatory role in the early stages of sexual arousal.
The clitoris may play a major role during sexual activity in that it is not only part of what makes the sexual act enjoyable for the woman but also enhances her response to coitus upon clitoral stimulation. Clitoral stimulation may induce local autonomic and somatic reflexes causing vaginal vasocongestion, engorgement, and subsequent transudation, lubricating the introital canal making the sexual act easier, more comfortable, and more pleasurable. The more stimulation, the higher the level of arousal and the easier it is to further increase stimulations.
Vasculogenic Female Sexual Dysfunction
Female sexual dysfunction has traditionally included disorders of desire/libido, disorders of arousal, pelvic pain disorders, and inhibited orgasm. Patient surveys estimate that 18-76% of adult women have such complaints during sexual activity. Female sexual dysfunction which may have its origin in abnormal arterial circulation into the vagina or clitoris during sexual stimulation, usually from atherosclerotic vascular disease may be considered a disorder of arousal. This vasculogenic female sexual dysfunction may include such clinical symptoms as delayed vaginal engorgement, diminished vaginal lubrication, pain or discomfort with intercourse, diminished vaginal sensation, diminished vaginal orgasm, diminished clitoral sensation or diminished clitoral orgasm. Traumatic injury to the ilio-hypogastric-pudendal arterial bed from pelvic fractures or blunt perineal trauma may also result in diminished vaginal/clitoral blood flow following sexual stimulation and fall into this vasculogenic category.
Prostaglandins
The prostaglandins are a series of cyclic derivatives of certain unsaturated fatty acids. They are found in a variety of tissues, including the prostate gland, the seminal vesicles, the lungs and the brain. These naturally occurring prostaglandins are derived by cyclization of 20-carbon unsaturated fatty acids such as arachidonic acid. See Lehninger, Albert L., Biochemistry, 2d ed. (1975), p. 300 (hereinafter xe2x80x9cLehningerxe2x80x9d).
Prostaglandins as a class of compounds have diverse pharmacologic activity, including stimulation of gastrointestinal and reproductive smooth muscle, relaxation and contraction of respiratory smooth muscle, hypotensive activity, inhibition of fatty acid lipolysis, inhibition of blood platelet aggregation, and inhibition of gastric acid secretion. Therapeutic utility of prostaglandins in general is correspondingly broad. As for prostaglandin E1 (xe2x80x9cPGE1xe2x80x9d) in particular, this compound, salts thereof, and lower alkyl esters thereof are well known and disclosed, e.g., in U.S. Pat. Nos. 3,069,322 (Bergstrom et al.), 5,219,885 (Froelich et al.) and in J. Org. Chem. 1974, 37, 2921. PGE1 has found utility in the treatment of peripheral occlusive diseases, acute myocardial infarction, angina pectoris, acute ischemic stroke, asthma, gastrointestinal ulcers, ulcers of the skin, and organ rejection. Various routes of administration have been described, including oral, intravenous, buccal, rectal, intraarterial, subcutaneous, and sublingual. The preferred route of administration of PGE1 will of course be dependent on the particular intended therapeutic use.
Prostaglandins are well known to those skilled in the art. This class of drugs includes those derivatives of prostanoic acid (5-octylcyclopentaneheptanoic acid) referred to as A-I series prostaglandins. Prostaglandin nomenclature is well known and disclosed, e.g., in page 409, Remington""s Pharmaceutical Sciences, 18th Edition, 1990, A. R. Gennaro, Ed., Mack Publishing Company, Easton, Pa. The term xe2x80x9cprostaglandinxe2x80x9d as used generically herein refers to the prostaglandin free acid and pharmaceutically acceptable derivatives thereof, including PGE1, PGA1, PGB1, PGF1xcex1, 19-hydroxy-PGA1, 19-hydroxy-PGB1, PGE2, PGA2, PGB2, 19-hydroxy-PGA2, 19-hydroxy-PGB2, PGE3, PGF3xcex1, carboprost tromethamine, dinoprost tromethamine, dinoprostone, lipoprost, gemeprost, metenoprost, sulprostone and tiaprost as well as salts and esters thereof. Preferred prostaglandins for use in the formulations of this invention include those prostaglandins comprising a xcex2-hydroxyketone moiety, including D-series and E-series prostaglandins, preferably E-series prostaglandins such as prostaglandin E1, including pharmaceutically acceptable salts and lower alkyl esters thereof (the term xe2x80x9clower alkylxe2x80x9d as used herein means straight chain or branched chain alkyl containing one to four carbon atoms). Of the lower alkyl esters, the ethyl ester of prostaglandin E1 (commercially available from Sigma Chemical Company, St. Louis, Mo., and preparable as disclosed, e.g., in U.S. Pat. No. 5,219,885, incorporated herein by reference) is preferred.
The biosynthesis of prostaglandins has been well characterized. See, e.g., Lehninger at p. 687. In a typical biosynthetic pathway, exemplified by production of PGE2, the essential fatty acid linoleic acid is converted into the 20-carbon arachidonic acid, which is then acted upon by prostaglandin synthase, a dioxygenase enzyme. Oxygen atoms are added at carbon atoms 9 and 15, and the product is cyclized by formation of a bond between carbon atoms 8 and 12. In the presence of reduced glutathione, this cyclized product undergoes conversion into prostaglandin PGE2. Other types of naturally occurring prostaglandins are derived from different polyunsaturated fatty acids.
In about the 1960s, prostaglandins were isolated from a particular species of Caribbean coral, which made them more widely available for research. Catanzarite, Valerian A. and Gary Aisenbrey, Contemporary OB/GYN (October 1987), p. 22. A large number of natural and synthetic analogues of the prostaglandins are now known. Lehninger at 687.
The prostaglandins are known to produce often unpredictable effects over a very wide range of biological activities of a hormonal or regulatory nature. Prostaglandins have been reported to both lower and raise blood pressure, to inhibit gastric secretion, dilate bronchi, inhibit lipolysis, antagonize vasopressin-induced anti-diarrhesis, constrict the pupil, increase and decrease the intraocular pressure and produce contraction of the uterus. See, e.g., Ganong, William F., Review of Medical Physiology, 7th ed. (1975), p. 226 (hereinafter xe2x80x9cGanongxe2x80x9d). The naturally occurring prostaglandins all appear to be capable of affecting the control of vascular and other smooth muscle contractions. In the central nervous system, prostaglandins are known to modify responses to certain synaptic transmitters. They have been reported to mimic the actions of some hormones and to inhibit the actions of certain others. See Ganong at 226.
Two of the most extensively studied of the prostaglandins are PGE2 and PGF2xcex1. Both of these molecules are synthesized within the pregnant and non-pregnant uterus. While PGE2 and PGF2xcex1 are similar in mediating some effects, they are different with respect to certain others. Both cause uterine contractions, but they predominate at different sites within the uterusxe2x80x94PGE2 in the lower uterine segment, PGF2xcex1 in the fundal region. Both play important roles during labor, but PGE2 has its major effect in cervical ripening, whereas PGF2xcex1 is more important in generating uterine contractions. PGE2 elevates body temperature, whereas PGF2xcex1 has no apparent effect on body temperature. PGE2 is vasodilator and bronchodilator, while PGF2xcex1 is a bronchoconstrictor and vasoconstrictor. See Catanzarite at 21-22.
Prostaglandins have been used in gynecology for pregnancy termination. Preparing the cervix with a prostaglandin suppository has been found to reduce the incidence of cervical laceration and significant bleeding. See Catanzarite at page 22. Synthetic analogues of prostaglandin PGE2, such as 16-16-dimethyl PGE2 and 9-methylene PGE2, have proven useful for the induction of first trimester abortions. Such procedures typically use vaginal suppositories containing 20 milligrams PGE2 or 3 milligrams of 15-methyl PGF2xcex1, or by repeated intramyometrial injections of 15-methyl PGF2xcex2, or by infusing a PGF2xcex1-urea mixture (20 milligrams of PGF2xcex1 and 40 milligrams of urea in 100 mL of 5% dextrose in water) into the amniotic sac.
In obstetrics, prostaglandins have been used for cervical ripening, labor induction and control of post-partum hemorrhage. Catanzarite at 29. For cervical ripening, PGE2 has been given intravenously, orally and vaginally, but the preferred route is intracervically. A PGE2 gel is now commercially available in Scandinavia, and another PGE2 gel is being investigated in the United States. The PGE2 gel can also be used for labor induction (3-5 mg of PGE2, prepared by blending a 20 mg suppository with 60 mL of lubricating jelly and using 9-15 mL of the mixture, is placed in the vagina). Catanzarite at 32. Prostaglandins have also been utilized to control postpartum hemorrhage.
Topical and transdermal drug formulations are designed to deliver a therapeutically effective amount of drug to or across the skin of a patient. Devices known to the art include reservoir type devices involving membranes that control the rate of drug release to the skin, gels and creams, and devices involving a dispersion of the drug in a matrix such as a pressure sensitive adhesive. As the skin presents a barrier to the drug it is often desirable or necessary to incorporate certain materials that enhance the rate at which the drug passes through the skin. For any particular drug, however, the type of device, the transdernal flux rate that is suitable, and suitable formulation components, are dependent upon the particular drug to be delivered.
Topical and transdermal administration of PGE1 and PGE1 derivatives have also been described, e.g., in U.S. Pat. No. 4,889,845 (Ritter et al.), U.S. Pat. No. 4,515,810 (Chow et al.), and U.S. Pat. No. 5,219,885 (Froelich et al.) and in Japanese Kokai 2-264725 (Morimoto et al.) and 63-135333 (Nakano et al.). In order for a transdermal formulation of PGE1 or a derivative thereof to be effective and suitable it is desirable that the formulation have a high transdermal flux rate, allowing a therapeutically effective blood level of the drug to be achieved or maintained when the formulation is applied to a relatively small area of the skin. Furthermore PGE1 readily undergoes certain reactions and rearrangements (see. e.g., J. Chromatography, 1991, 555, 73 (Lee et al.). This instability of the prostaglandin can be problematic in providing a suitable transdermal formulation.
The invention provides topical compositions and methods of treatment for female sexual dysfunction. The invention also provides methods for ameliorating female sexual dysfunction by modulating arousal and the excitation and plateau phases of the female sexual response on demand by topical application of an effective amount of prostaglandin E1.
The composition of the invention is suitable for topical application, and comprises a vasoactive agent, preferably a prostaglandin, more preferably prostaglandin E1, a polymer thickener, a lipophilic component, and an acidic buffer system. In several preferred embodiments, the polymer thickener is a polyacrylic acid polymer. In other preferred embodiments, the polymer thickener is a polysaccharide gum. The lipophilic component is chosen from the group consisting of the C1 to C8, aliphatic alcohols, the C2 to C30 aliphatic esters and mixtures thereof. The acidic buffer system is chosen to provide a suitable pH to minimize irritation of skin and mucous membranes. The composition is typically in the form of a cream, lotion, gel or other form suitable for topical application to skin and mucous membranes.
The prostaglandin is present in a formulation of the invention in a therapeutically effective amount. Therapeutic effectiveness can be assessed, in part, with increase in vaginal secretion, increase in vaginal engorgement, increase in sexual responsiveness and increase in arousal.
The present invention provides the use of compositions comprising prostaglandin E1 for the manufacture of a medicament for topical or transdermal administration to modulate sexual response in a human female. While not being tied to a specific mechanism, it is believed that prostaglandin E1 acts directly on local tissues to produce increases in vaginal secretion, increases in vaginal engorgement, and acts indirectly on the central nervous system to increase sexual responsiveness and arousal.
The methods of the present invention may be used to improve or enhance arousal and sexual response in women whose sexual response is impaired as evidenced by diminished capacity to produce sufficient vaginal lubrication to facilitate comfortable penile penetration and by other symptoms of impaired sexual responsiveness. The invention thus provides a method of ameliorating female sexual arousal disorder, comprising the step of administering to a human female a composition suitable for topical application comprising an effective amount of a prostaglandin, a polymer carrier, a lipophilic component, and a buffer system, typically in a cream, lotion, gel or other suitable form.
The effective amount of prostaglandin to be administered is selected to provide increased blood flow to the genitalia, which may be assessed by visual inspection, vaginal photoplethysmography, vaginal lubrication or engorgement. Alternatively, the effective amount to be administered is selected to provide increased sexual response, which may be assessed by visual inspection, vaginal photoplethysmography, vaginal lubrication and engorgement of the genitalia.
The effective amount of prostaglandin to be administered to increase arousal is selected to provide increased arousal as measured by self-report by a suitable questionnaire.
In the absence of any clinically diagnosed dysfunction in the female sexual response, the methods of the present invention may also be used to enhance the sexual response in a human female not suffering from a sexual dysfunction. The present invention will allow a more rapid response to sexual stimulation along with heightened sensation associated with excitement and plateau stages of the female sexual response by virtue of the increased blood flow to the tissues, as well as enhance subjective aspects, thereby leading to relatively increased arousal. The invention thus provides a method of enhancing female sexual arousal, comprising the step of administering to a human female a composition suitable for topical application comprising an effective amount of a prostaglandin, a polymer carrier, a lipophilic component, and a buffer system, typically in a cream, lotion, gel or other suitable form.
The invention further provides a method of enhancing female sexual response, comprising the step of administering to a human female a composition suitable for topical application comprising an effective amount of a prostaglandin, a polymer carrier, a lipophilic component, and a buffer system, typically in a cream, lotion, gel or other suitable form.
The invention also provides an article of manufacture comprising a container having a closure, a composition suitable for topical application comprising prostaglandin E1 and a label that provides instructions for use in human females. Suitable containers include tubes, jars, vials and unit dosage forms. The closure may be recloseable, for example, a screw cap or a tight snap-fit cap.